Title of Invention

A PROCESS FOR THE PREPARATION OF TOPICAL FORMULATION FOR PREVENTION OF PERIPHERAL VASCULAR DISEASES

Abstract

The present invention relates to a topical formulation and a process for the preparation thereof, which can be used in management (including prevention) of peripheral vascular disease and conditions and syndromes causing or likely to cause peripheral vascular disease, particularly those involving microcirculation or microvasculature of hands and feet The topical formulation of the present invention is helpful in diseases like cold injuries, diabetes mellitus, Berger's disease, Raynaud's phenomenon, burns and other vasospastic, vasodestructive or ischemic conditions related to infective, autoimmune, neural vascular, degenerative or inflammatory disorders. The topical formulation, on multiple applications to the overlying skin, increases the local blood supply, and may reduce inflammation, intravascular thrombosis & clotting, and viscosity of the blood, thus, improving the blood flow in the lesion area The formulation helps in relieving the painful ischemic symptoms, in preventing or reducing further damages to the tissues, and in preventing or reducing oxidation injury. It also causes early healing and increase work efficiency of the body part The formulation has no significant adverse-effects and can be used in cold and dry weather

Full Text

FIELD OF THE INVENTION The present/invention -relates tea-topical: formulation for prevention and management of cold injuries and other peripheral vascular diseases, specifically but without implying any limitation thereof, those afflicting microvasculature or microcirculation. PRIOR ART Vasospastic / vasodestructive or ischemic disorders of limbs are very common. These are found even in apparently normal individuals, and occur due to transient or permanent reduction of blood supply and oxygen at tissue level. This occurs more frequently and severely in cold injuries, cold sensitivity, diabetes mellitus, Berger's disease, Raynaud's phenomenon, -bums, arteritis of all types and other such diseases coming under the broad category of peripheral vascular diseases, particularly involving microcirculation or microvasculature. Hypovolemia, atherosclerosis, anemia and old age are further risk factors. Thrombosis in microvasculature of hands or feet further complicates this, leading to more reduction in blood & oxygen supply and permanent damage of the tissues. Further, it can lead to tissue death, gangrene and loss of limb or function. More further, the condition becomes worse in cold weather, particularly at high altitude, more particularly in old individuals and those who use tobacco products and in patients with conditions described as above. Another related problem or complication is that local ischemia leads to development of infection and inflammation thai further causes more local ischemia leading to a vicious cycle. These peripheral vascular diseases could be of different pathological origins, namely autoimmune, infective, environmental, toxic, autonomic, vascular, idiopathic and of other and unknown origins. The disorders as described above lead to acute pain, cyanosis and loss of work efficiency (particularly of arms & legs, hands & fingers, feet & toes or facial parts) leading to edema and ulcer formation, leading to muscle and bone death, deep-seated infection, amputation and ultimately loss of the affected body organ. Even when the local blood and Oxygen supply is partially restored by conventional treatment, the tissue injury aggravates due to oxidative mechanisms. Barring the very mild injuries, the damage at microvascular or microciculation level is permanent and may be progressive.Most of the predisposing or precipitating factors are either accidental or unpreventable. One of the non-pharmacological methods known in the art for preventing aggravation or treating peripheral vascular diseases (of the microcirculation), particularly cold-injuries, is by providing physical barrier offered by clothing, particularly to hand and feet. This method is however inadequate in extremely cold conditions, particularly in individuals who are old, have a preceding microvascular condition or use tobacco products and is inconvenient in carrying out routine work. Another non-pharmacological method known in the art for preventing or treating peripheral vascular diseases, particularly the cold injury, is slow re-warming of the affected part in water, called thawing. A practical limitation with of the above method is that it cannot be used as a preventive routinely but can only be used as a management .of the condition. Another drawback is that it is neither practical nor possible io use it as the main treatment in field conditions. Still another limitation of the above method is that it may be useful only in cold injuries and not other forms of peripheral vasospastic / ischemic diseases. Even in cold injuries, it is useful for only mild cold injuries but is considered inadequate in major cold injuries (frostbite). A pharmacological method known in the art, is systemic i.e. oral, intramuscular or intravenous administration of vasodilator drugs. However, there is disagreement about its benefit in treating local micro-vascular conditions (mostly of arms & legs or hands and feet) due to inability of the systemic route to deliver sufficient quantity of medication to the peripheral ischemic lesion because of large volume of distribution. Another drawback of the above method is that a very high dose is required for achieving the desired effect. Still another drawback is that there may not be any benefit at all if blood supply to the hand/foot is already blocked significantly due to thrombosis. Further drawback of the above method is that the high dosage required for systemic route causes serious side effects like low blood pressure and significant palpitation and heart problems which limits the duration of treatment to a few days only, thereby limiting the benefit.. Yet another drawback of the above method is the high cost involved due to high dose requirement for managing the disease. Still further drawback of the above method is that systemic vasodilator therapy becomes reserved for very severe cases only, and not suited in a majority of patients that have mild to moderate problem. Another method, known in the art, for management of the above diseases is systemic administration of anticoaggulant / thrombolytic agents. However, like systemic administration of vasodilators, the above method of management has the drawback that it requires a very high dosage thereby increasing side effects (bleeding from unrelated sites) and cost. Another drawback of this method is that its use is considered dangerous except in hospital conditions. Yet another drawback of this method is that it cannot be used in chronic or recurring conditions and their use at present is therefore limited to most severe cases considering the risks involved. A rurtner method, known in the art, for management of the above diseases is systemic administration of antiplatelet drugs like dipyridamole or aspirin. However, like systemic administration of vasodilators, the above method of management also suffers from the disadvantage that it requires a very high dosage thereby increasing side effects and cost. Another drawback of the above method is that its pharmacological effect becomes limited if local blood circulation is compromised due to thrombosis. Yet another method of management, known in the art, is oral pentoxyphyllin or other Xanthine-based drugs or Dextran infusion that are known to reduce blood viscosity and thereby enabling more flow of blood to the lesions. However, the above method, like systemic vasodilators and antiplatelet drugs, suffers from the disadvantage that a very high blood concentration is required for optimal concentration in the peripheral lesions, thus increasing side effects and cost. Further, it may have limited pharmacological effect if local blood circulation is compromised due to thrombosis. Still further method, known in the art, for the management of the above diseases is the topical application of nifedipine ointment for treating Raynaud's disease. However, this method has not been found very effective in the above-mentioned condition. Another drawback of the above method is that it is not commercially available in many countries including India. Topical ointments containing analgesics & antibiotics are available for the management but these are useful in controlling only the infection and these do not address the main problem of microvascular insufficiency. Topical ointments containing nicotinic acid as a vasodilator (for example, Thrombophobe') are available in the market for treating microvascular insufficiency through topical application and are being clinically used. However, this also suffers from the drawback that although useful, these are usually not found potent enough to cure the conditions by themselves and are used as a supportive treatment approach only. Thus, there is a need to overcome the limitations of the systemic method of management of disease arising out of its inability to deliver sufficient quantities of medication to the microvasculature (say, of hands and feet) without serious systemic side-effects. There is need for a topical ointment which could penetrate effectively through the skin to deliver drugs that act on local microvasculature and increase the local blood flow through vasodilation and other effects. OBJECTS OF THE INVENTION Primary object of the invention is to provide a topical formulation, and a process for preparation thereof, for prevention and management of peripheral vascular diseases. Another object of the invention is to provide a topical formulation, and a process for preparation thereof, for prevention and management of peripheral vascular diseases, that can be effective in extremes of atmospheric temperature, pressure and humidity. Still another object of the invention is to provide a topical formulation, and a process for preparation thereof, for prevention and management of peripheral vascular diseases, that can be effective even on hard and course skin and when the skin cover is broken. Yet another object of the invention is to provide a topical formulation, and a process of preparation thereof, for prevention and management of peripheral vascutar diseases which is easy to perform. Still further object of the invention is to provide a topical formulation, and a process for preparation thereof, for prevention and management of peripheral vascular diseases, that increases the local blood circulation by virtue of vasodilation .'n the local microcirculation. Yet further object of the invention is to provide a topical formulation and a process for preparation thereof, for prevention and management of peripheral vascular diseases, that may reduce the blood viscosity, reduce platelet aggregation, prevent intravascular clotting and help in reducing oxidative injury on revascularization in the local microvasculature. Still further object of the invention is to provide a topical formulation, and a process for preparation thereof, for prevention and management of peripheral vascular diseases, which hejps in faster pain relief and healing time. According to this invention there is provided a process for the preparation of topical formulation for prevention and management of peripheral vascular diseases comprising the steps of : a) preparing oil phase by mixing cetostearyl alcohol and liquid paraffin to white soft paraffin followed by melting and mixing kept at a temperature between 45-65°C and adding dipyridamol; b) preparing aqueous phase by dissolving sodium lauryl sulphate or citrate and chlorocresol in water, adding extract of Aloe Soc and heating preferably at less than 65°C and adding active components like citrate preferably citric acid, niacin, preferably nicotinic acid, and pentoxyphyllin; c) mixing the separately pre-heated oil phase prepared in step (a) and aqueous phase prepared in step (b) to less than 65°C, cooling it to about 30-40°C and adding ascorbic acid and perfume. A main active ingredient of the formulation of the present invention is Aloe Soc. mother tincture. Other preferred active ingredients of the topical formulation include citrate, particularly its acid, ascorbate, particularly its acid, and niacin, more preferably, nicotinic acid. Still other preferred ingredients are pentoxyphyllin and dipyridamole. The formulation also includes several inert base substances which are helpful in maintaining the active components in a state that ensures derma! permeability, sustained action and integrity of the ointment. The base materials of the formulation include paraffins, alcohols, a surfactant, a hygroscopic agent, a stabilizer and some perfume. The preferred solvent of the base materials is refined water, making the formulation an oil-in-water emulsion preparation. The topical formulation is prepared by making an oil-phase and aqueous phase separately and mixing the two in a determined fashion and adding the active ingredient(s) in a determined way. The oil phase and water phase are maintained at less than 65°C. Aqueous phase is poured in oil phase with continuous stirring. The complex is cooled to 35°C or even lower after which glycerin and preferably ascorbic acid in powder form, and perfume are added as the last step of the formulation, again with continuous stirring. The topical formulation of the present invention is prepared by the process comprising of the following steps: a} Preparation of oil phase The oil phase is prepared by mixing cetostearyl alcohol 0.97-20.1 % weight wise and liquid paraffin 0.97-20.1 % wt wise to white soft paraffin 2.4-50% wt wise followed by melting and mixing these on water bath kept at a temperature between 45-65 °C and adding up to 4% wt wise dipyridamol; b) Preparation-of aqueous phase The aqueous phase is made by dissolving sodium lauryl sulphate or citrate 0.24-4% wt wise and chlorocresol 0.02-0.4% wt wise in water (30-90 ml) and adding 20% w/v extract of Aloe Soc 4.8%-80% heating on a water bath preferably at less than 65 °C. Other preferable active components like Citrate, preferably citric acid up to 10% wt wise, niacin, preferably nicotinic acid up to 6% wt wise, and pentoxyphyllin up to 10% wt wise are added to the aqueous phase before the heat treatment. c) Preparation of formulation Oil phase and the aqueous phase prepared as above are separately maintained preferably at a temperature less than 65 °C. Aqueous phase is poured in oil phase with continuous stirring. The complex is cooled at 30-40 °C following which glycerin (100-1000mg) and preferably ascorbic acid as powder (300-3000 mg) are mixed with continuous but not vigorous stirring before adding a small quantity of compatible perfume. The invention will now be illustrated with a working example, which is intending to be an illustrative example, and is not intending to be taken restrictively to Imply any limitation on the scope of the present invention. WORKING EXAMPLE 2.5 gram cetostearyl alcohol and 15 gram white soft paraffin are melted on water bath in the decreasing order of their melting points. 5 gram liquid paraffin & 15 gram of Aloe Soc mother tincture are added and the entire content is heated to 60 °C to prepare the oil phase. Next, 2 gram sodium lauryl sulphate and 100 mg chlorocresol are added in 75 gram water and the entire contents are heated on a water bath to prepare the water phase. The oil phase and water phase are heated to 60 °C. The aqueous phase is poured in oil phase with continuous stirring. After cooling it to 35 °C, 1 gram glycerin and 2 gram ascorbic acid powder are added . CLINICAL EVALUATION The vasodilator action of the Aloe Soc mother tincture-based multi-component medicated ointment was tested using nuclear medicine technology in five healthy volunteers. Digital angiographic and / or btood-pool images of the hands and / or feet were taken after injecting a radiopharmaceutical on a Gamma or SPECT Camera. After applying the 2 gram of medicated ointment on the surface on one hand / feet and gently rubbing to spread it completely, the nuclear medicine images were taken frequently to test whether and by how much the vascularity of the part has increased following the ointment application and at what interval. Typically,-the imaging protocol was repeated before and after 1-3 days of application (two times a day) to evaluate the benefit qualitatively and quantitatively. All the five individuals showed more than 40% (40-90%) increase in blood flow in the part of application within 48-72hrs of the topical application. All patients developed feeling of warmth over the part applied to. There were no side effects noted in any of the patients. Phase 1-2 field trial at high altitude in more than 25 patient volunteers has shown reduction in pain & numbness and increase in feeling of warmth & skin temperature by 0.5-2 C following topical application. No local or systemic side effects have been observed. It is understood that the process of the present invention is susceptible to modifications, changes, adaptations by those skilled in the art. Such modifications, changes adaptations are intended to be within the scope of the present invention which is further set forth under the following claims: WE CLAIM 1. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases comprising the steps of: a) preparing oil phase by mixing cetostearyl alcohol and liquid paraffin to white soft paraffin followed by melting and mixing kept at a temperature between 45-65°C and adding dipyridamol; b) preparing aqueous phase by dissolving sodium lauryl sulphate or citrate and chlorocresol in water, adding extract of Aloe Soc and heating preferably at less than 65°C and adding active components like citrate preferably citric acid, niacin, preferably nicotinic acid, and pentoxyphyllin; c) mixing the separately pre-heated oil phase prepared in step (a) and aqueous phase prepared in step (b) to less than 65°C, cooling it to about 30-40°C and adding ascorbic acid and perfume. 2 A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in claim 1 wherein the said cetostearyl alcohol is taken in the quantity of 0.97-20.1% by weight of the said topical formulation 3 A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in claim 1 wherein the said liquid paraffin is taken in the quantity of 0.97-20.1% by weight of the said topical formulation. 4 A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in claim 1 wherein the said white paraffin is taken in the quantity of 2.4-50% by weight of the said topical formulation. 5. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in claim 1 wherein the said aloe soc mother tincture is taken in the quantity of 4.8-80% by weight of the said topical formulation. 6 A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in claim 1 wherein the said sodium lauryl sulphate is taken in the quantity of 0.24-4% by weight of the said topical formulation. 7. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said Chlorocresol is taken in the quantity of 0.02-0.4% by weight of the said topical formulation. 8. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said glycerin is taken in the quantity of 0.4%-2% by weight of the said topical formulation.. 9. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said dipyridamole is taken in the quantity up to 4% by weight of the said topical formulation. 10. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said nicotinic acid is'taken in the quantity up to 6% by weight of the said topical formulation.. 11. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said citric acid is taken in the quantity up to 10% by weight of the said topical formulation. 12. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said pentoxyphyllin is taken in the quantity up to 10% by weight of the said topical formulation. 13. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the said ascorbic acid is taken in the quantity of 1-5% by weight of the said topical formulation. 14. A process for the preparation of topical formulation for prevention and management of peripheral vascular diseases as claimed in Claim 1 wherein the rest of the weight and volume of the said topical formulation is provided by the said purified water. 15. A topical formulation for prevention and management of peripheral vascular diseases comprising Aloe Soc mother tincture, citric acid, ascorbic acid, nicotinic acid, pentoxyphyllin, dipyridamole and inert base materiaf comprising of cetostearyl alcohol, soft white paraffin, liquid paraffin, sodium-lauryl sulphate/citrate, water and chlorocresol. 16. A topical formulation tor prevention and management of peripheral vascular diseases comprising cetostearyl alcohal 0.97%-20.1% by weight, liquid paraffin 0.97-20.1% by weight , soft white paraffin 2.4-50% by weight , Aloe Soc mother tincture 4.8-80% by weight , sodium lauryl sulphate 0.24-4% by weight , Chlorocresol 0.02-0.4% by weight, glycerin 0.04%-2% by weight, dipyridamole up to 4% by weight, nicotinic acid up to -6% by weight, citric acid up to 10% by weight, pentoxyphyllin up to 10% by weight, ascorbic acid 1-5% by weight. 17. A topical formulation for prevention and management of peripheral vascular diseases and a process for preparation thereof substantially as described and exemplified herein.

Documents:

431-DEL-2004-Abstract-(27-04-2007).pdf

431-del-2004-abstract.pdf

431-del-2004-claims.pdf

431-DEL-2004-Correspondence-Others-(09-12-2005).pdf

431-DEL-2004-Correspondence-Others-(10-03-2008).pdf

431-DEL-2004-Correspondence-Others-(12-03-2004).pdf

431-del-2004-correspondence-others-(27-04-2007).pdf

431-del-2004-correspondence-others.pdf

431-DEL-2004-Correspondence-PO-(09-04-2007).pdf

431-DEL-2004-Correspondence-PO-(26-03-2004).pdf

431-del-2004-correspondence.pdf

431-del-2004-description.pdf

431-DEL-2004-Form-1-(12-03-2004).pdf

431-DEL-2004-Form-18-(09-12-2005).pdf

431-del-2004-form-18.pdf

431-DEL-2004-Form-3-(27-04-2007).pdf

431-del-2004-form1.pdf

431-del-2004-form2.pdf

431-DEL-2004-GPA-(10-03-2008).pdf